Opiate drug abuse is a critical contributor to the global AIDS epidemic, and over a third of HIV infections in the U.S. can be linked to intravenous drug abuse. Recent estimates suggest that almost 20% of intravenous drug abusers are infected with HIV. Tobacco smoking is prevalent in HIV-infected patients, and is very common among intravenous drug abusers. Importantly, smoking is strongly associated with a number of non-AIDS conditions, including chronic obstructive lung disease (COPD), and this chronic inflammatory disease may contribute to the development of neuroinflammation associated with HIV infection. However, there is very little known about the combined effects of tobacco smoke and chronic opioid administration on the development of inflammatory responses, and even less known about the effects of these clinically relevant drugs on the development of neurodegeneration following HIV infection. We describe preliminary data which shows that the inflammatory response is both quantitatively and qualitatively distinct following the combination of tobacco and opiate administration. We propose to conduct experiments using humanized mice to examine the combined effects of chronic tobacco smoke exposure with and without chronic administration of morphine on the development of HIV-induced neuroinflammation. Our published and preliminary data show that the blood-brain barrier is a target for the effects of opiates and/or tobacco, as well as the inflammatory activity of monocytes and macrophages. We propose to investigate the mechanistic basis for the combined effects of these drug treatments on these cell populations. We believe the proposed studies will provide highly novel information about the effects of morphine and tobacco smoke on HIV-associated neurodegeneration in a clinically relevant immunological context.